Biomaterial Database

Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders. 2023

Alfredo M Valencia, and Akshay Sankar, and Pleuntje J van der Sluijs, and F Kyle Satterstrom, and Jack Fu, and Michael E Talkowski, and Samantha A Schrier Vergano, and Gijs W E Santen, and Cigall Kadoch

Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.

UI	MeSH Term	Description	Entries
D008322	Mammals	Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.	Mammalia,Mammal
D009707	Nucleosomes	The repeating structural units of chromatin, each consisting of approximately 200 base pairs of DNA wound around a protein core. This core is composed of the histones H2A, H2B, H3, and H4.	Dinucleosomes,Polynucleosomes,Dinucleosome,Nucleosome,Polynucleosome
D002843	Chromatin	The material of CHROMOSOMES. It is a complex of DNA; HISTONES; and nonhistone proteins (CHROMOSOMAL PROTEINS, NON-HISTONE) found within the nucleus of a cell.	Chromatins
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D014157	Transcription Factors	Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.	Transcription Factor,Factor, Transcription,Factors, Transcription
D042002	Chromatin Assembly and Disassembly	The mechanisms effecting establishment, maintenance, and modification of that specific physical conformation of CHROMATIN determining the transcriptional accessibility or inaccessibility of the DNA.	Chromatin Remodeling,Chromatin Assembly,Chromatin Disassembly,Chromatin Modeling,Chromatin Disassemblies,Disassembly, Chromatin,Remodeling, Chromatin
D065886	Neurodevelopmental Disorders	These are a group of conditions with onset in the developmental period. The disorders typically manifest early in development, often before the child enters grade school, and are characterized by developmental deficits that produce impairments of personal, social, academic, or occupational functioning. (From DSM-5).	Mental Disorders Usually Diagnosed in Infancy, Childhood or Adolescence,Neurodevelopmental Disorders Usually Diagnosed in Infancy, Childhood or Adolescence,Child Mental Disorders,Mental Disorders Diagnosed in Childhood,Child Mental Disorder,Disorder, Child Mental,Disorder, Neurodevelopmental,Mental Disorder, Child,Mental Disorders, Child,Neurodevelopmental Disorder